Halogenation

Another chemical consequence of the enolization of aldehydes and ketones is their halogenation at the α position. It can take place either through the enol or through the enolate.

Halogenation of enols

How is 2-methylcyclohexanone halogenated? It has two positions α to the carbonyl, so… why is the reaction regioselective?

Chlorination of 2-methylcyclohexanone in acid: 2-chloro-2-methylcyclohexanone

Experimentally, it is found that:

1. The reaction rate is first order in the substrate.

Therefore, the halogen does not appear in the rate equation at all (the rate is the same whether the reaction is carried out with Cl₂, Br₂ or I₂).

2. The reaction shows a positive isotope effect (k_H/k_D > 1).

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A mechanism compatible with these experimental data must involve only the substrate, not the halogen, in the rate-limiting step.

Besides, the C–H bond must be broken in that step, because otherwise no isotope effect would be observed.

Enol formation must therefore be the rate-limiting step (highest TS): it involves only the substrate, and the C_α–H bond is broken in it.

The two enols of 2-methylcyclohexanone: the more substituted one is 4 kcal/mol more stable

Of the two possible enols, the more substituted one is the more stable.

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An energy difference of 4 kcal/mol has been measured between the two enols, which means that, at room temperature, the proportion of the more stable enol (enol-2) is higher than 99.5%. Use the equations to check it.

Equations: ΔG° = −RT ln K; K = e^(−ΔG°/RT); K = [enol 2]/[enol 6]

Attack of the enol on the halogen: carbocation stabilized by the oxygen versus the much less stable tertiary carbocation

This is another example of how an oxygen atom can stabilize an adjacent positive charge: the oxygen of an alcohol or an ether is an electron donor when it is attached to an sp² carbon, such as that of a carbocation.

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The halogen behaves as an electrophile. The double bond of the enol shares electrons with one of the halogen atoms, while the other halogen keeps the electrons of the X–X bond, so that both complete their octets. The attack on the enol can take place in two ways, but it follows the easiest path, i.e. through the less unstable carbocation.

Finally, the loss of a proton (which forms HX with the released halide) gives 2-chloro-2-methylcyclohexanone.

Loss of HX giving the 2-halo-2-methylcyclohexanone

The overall energy diagram along the reaction coordinate is qualitatively like this one:

Energy diagram of the halogenation of 2-methylcyclohexanone: enolization is the rate-limiting step

The experimental data point to enolization as the rate-limiting step. Only the substrate, not the halogen, appears in the rate law, which means that halogenation must take place in lower-energy steps. The positive isotope effect indicates that the key C–H bond must be broken precisely in the rate-limiting step.

Halogenation of enolates

The halogenation of aldehydes or ketones in basic medium, through their enolate ions, is more problematic because it usually gives complex mixtures of products. Polyhalogenation cannot be avoided!

Halogenation in basic medium: the monohalogenated product has a more acidic hydrogen and is halogenated again

The result is a mixture as in this example:

Bromination of cyclohexanone with Br₂/HO⁻: mixture of 2-bromo-, 2,2-dibromocyclohexanone and 1,2-cyclohexanedione

The α-gem-dihalo derivative formed can even evolve into a diketone, through a reaction we have already seen.

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